US7199106B2ExpiredUtilityPatentIndex 83
Lincomycin derivatives possessing antimicrobial activity
Est. expiryJun 17, 2023(expired)· nominal 20-yr term from priority
C07D 405/12
83
PatentIndex Score
11
Cited by
101
References
29
Claims
Abstract
Novel lincomycin derivatives are disclosed. These lincomycin derivatives exhibit antibacterial activity. The compounds of the subject invention may exhibit potent activities against bacteria, including gram positive organisms, and may be useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.
Claims
exact text as granted — not AI-modified1. A compound of Formula (IA):
wherein:
the
represents a bond that may be a double bond or a single bond;
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl, (alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is selected from the group consisting of hydrogen and alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substitutedalkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and wherein m=0–2;
and wherein t=0–3;
or pharmaceutically acceptable salts and/or prodrugs thereof;
with the proviso excluding the following compounds:
the compounds when
is a single bond and each R 9 is hydrogen;
and the compounds when
is a single bond, R 9 is substituted alkyl having a single substituent said single substituent is other than halo, oxygen, hydroxy, primary amine, amine(secondary alkyl substituted by alkyl above), amine (tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or
—(CH 2 ) n NR′R″ where n is an integer of from 1 to 8 and R′ and R″ are hydrogen or alkyl; and the compounds when
is a single bond, R 9 is halo.
2. A compound of Formula (IA):
wherein:
the
represents a bond that may be a double bond or a single bond;
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl, (alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is selected from the group consisting of hydrogen and alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substituted alkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and wherein m=0–2;
and wherein t=0–3;
or pharmaceutically acceptable salts and/or prodrugs thereof;
with the proviso excluding the following compounds:
the compounds when
is a single bond and each R 9 is hydrogen;
and the compounds when
is a single bond, R 9 is substituted alkyl having a single substituent said single substituent is other than halo, oxygen, hydroxy, primary amine, amine(secondary alkyl substituted by alkyl above), amine (tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or
—(CH 2 ) n NR′R″ where n is an integer of from 1 to 8 and R′ and R″ are hydrogen or alkyl;
and the compounds when
is a single bond, R 9 is halo.
3. The compound of either claim 1 or 2 wherein wherein the nitrogen-containing ring in Formulas (I) and (II) is selected from:
4. A compound selected from the group consisting of:
1-(2-(S)-4-(S)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(R)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(R)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-chloro-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-chloro-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(3-p-fluorophenyl)thiopyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(n-butylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(3,3,3-trifluoroprop-1-yl-thio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(2-(2-chlorophenyl)-ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(3-methylbut-1-ylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(2-ethoxythiol)-ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(2,2,2-trifluoroethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(m-methylphenyl)methylsulfanylpyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(p-pyridinylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(p-trifluoromethoxyphenyl)methylsulfanyl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(o,p-dichlorophenyl)methylsulfanyl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
1-(2-(S)-4-(S)-(p-pyridinylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;
4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methlylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-acetic acid methyl ester;
1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid ethyl ester;
4-(3-Cyano-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propylidene-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide; and
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4 5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Fluoro-phenylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3,3,3-Trifluoro-propylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2-Chloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methyl-butylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(2-Mercapto-ethoxy)-ethylsulfanyl]-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,2,2-Trifluoro-ethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyridin-4-ylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Trifluoromethoxy-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-acetic acid methyl ester;
1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid ethyl ester;
4-(3-Cyano-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propylidene-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide; and
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.
5. A compound of Formula (IB):
wherein:
R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is H, alkyl, or hydroxyalkyl;
R 7 is H or alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, —(CH 2 ) n —OH, —(CH 2 ) n —NR 4 R 5 , and branched chain isomers thereof wherein n is an integer of from 1 to 8 inclusive and R 4 and R 5 are H or alkyl; and
m is 1 or 2;
or a prodrug and/or a pharmaceutically acceptable salt thereof;
with the proviso that the compound of formula I has a minimum inhibition concentration of 32 μg/mL or less against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron , and Clostridium difficile.
6. A compound selected from the group consisting of:
4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Hydroxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-piperidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Pentyl-pyrrolidine-2-carboxylic acid [1-(6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;
4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
Phosphoric acid mono-(4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl) ester;
Hexadecanoic acid 4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-yl ester;
Phosphoric acid mono-(4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl) ester;
Hexadecanoic acid 4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-yl ester;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
4-Propyl-pyrrolidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Propyl-pyrrolidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-pyrrolidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(2-methylsulfanyl-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Propyl-pyrrolidine-2-carboxylic acid [1-(6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;
or a prodrug and/or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1 , 2 or 5 .
8. A method for the treatment of bacterial infection in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 , 2 or 5 .
9. A method for the treatment of bacterial infection in a mammal comprising administering to the mammal a pharmaceutical composition of claim 7 .
10. The method according to claim 9 , wherein the compound is administered to the mammal orally, parenterally, transdermally, topically, rectally, or intranasally in a pharmaceutical composition.
11. The method according to claim 9 , wherein the compound is administered in an amount of from about 0.1 to about 100 mg/kg body weight/day.
12. A compound of Formula (I):
wherein:
W is a nitrogen-containing ring:
m is 0, 1, 2 or 3; wherein when m is 2, the nitrogen-containing ring may optionally contain a double bond between the 4 and 5 nitrogen-containing ring positions; wherein when m is 3, the nitrogen-containing ring may optionally contain one double bond between either the 4 and 5 nitrogen-containing ring positions or between the 5 and 6 nitrogen-containing ring positions; wherein the nitrogen-containing ring positions are consecutively numbered counterclockwise beginning with “1” at the nitrogen;
R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent, or one of R 2 and R 3 is ═CH 2 and the other is absent;
R 6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is H or alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclicsulfanylalkyl, heteroarylsulfanyl, and heterocyclicsulfanyl, propylidene (═CHCH 2 CH 3 ), azido, —(CH 2 ) n —OH, —(CH 2 ) n —NR 4 R 5 , and branched chain isomers thereof wherein n is an integer of from 1 to 8 inclusive and R 4 and R 5 are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein not more than one —S(O) q R 13 group is present on the nitrogen-containing ring;
and wherein t=0–3;
or a prodrug and/or pharmaceutically acceptable salt thereof;
with the proviso excluding the following compounds:
the compounds when
is a single bond and each R 9 is hydrogen;
and the compounds when
is a single bond, R 9 is substituted alkyl having a single substituent said single substituent is other than halo, oxygen, hydroxy, primary amine, amine(secondary alkyl substituted by alkyl above), amine (tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or
—(CH 2 ) n NR′R″ where n is an integer of from 1 to 8 and R′ and R″ are hydrogen or alkyl; and the compounds when
is a single bond, R 9 is halo.
13. A compound of Formula (IA):
wherein:
the
represents a bond that may be a double bond or a single bond;
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is selected from the group consisting of hydrogen, alkyl substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl, (alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is selected from the group consisting of hydrogen and alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substitutedalkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and wherein m=0–2;
and wherein t=0–3;
or pharmaceutically acceptable salts and/or prodrugs thereof;
with the proviso excluding the following compounds:
the compounds when
is a single bond and each R 9 is hydrogen;
and the compounds when
is a single bond, R 9 is substituted alkyl having a single substituent said single substituent is other than halo, oxygen, hydroxy, primary amine, amine(secondary alkyl substituted by alkyl above), amine (tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or
—(CH 2 ) n NR′R″ where n is an integer of from 1 to 8 and R′ and R″ are hydrogen or alkyl; and the compounds when
is a single bond, R 9 is halo.
14. A compound of Formula (IA):
wherein:
the
represents a bond that may be a double bond or a single bond;
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl, (alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is selected from the group consisting of hydrogen and alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, substituted alkyl, halo, substituted alkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and wherein m=0–2;
and wherein t=0–3;
or pharmaceutically acceptable salts and/or prodrugs thereof;
with the proviso excluding the following compounds:
the compounds when
is a single bond and each R 9 is hydrogen;
and the compounds when
is a single bond, R 9 is substituted alkyl having a single substituent said single substituent is other than halo, oxygen, hydroxy, primary amine, amine(secondary alkyl substituted by alkyl above), amine (tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or
—(CH 2 ) n NR′R″ where n is an integer of from 1 to 8 and R′ and R″ are hydrogen or alkyl;
and the compounds when
is a single bond, R 9 is halo.
15. A compound of Formula (IA):
wherein:
the
represents a bond that may be a double bond or a single bond;
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent, or one of R 2 and R 3 is ═CH 2 and the other is absent;
R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl,
—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl,
—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl,
or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is selected from the group consisting of hydrogen and alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, aryl, substituted aryl, alkenyl, substituted alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and wherein m 1 =0–2;
and wherein t=0–3;
or pharmaceutically acceptable salts and/or prodrugs thereof;
with the following provisos:
A. that in the compounds of formula (I) when
is a single bond,
m 1 is zero or one,
R 2 and R 3 are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkyl or one of R 2 and R 3 is ═NOR 7 and the other is absent, or one of R 2 and R 3 is ═CH 2 and the other is absent,
R 6 is hydrogen, alkyl, hydroxyalkyl, —C(O)O-alkylene-cycloalkyl, —C(O)O-alkylene-substituted alkyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, —C(O)O-substituted hetercyclic, —[C(O)O] p -alkylene-heterocycle, —[C(O)O] p -alkylene-substituted heterocycle, where p is zero or one, and
R 7 is selected from the group consisting of hydrogen and alkyl;
R 9 is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, —(CH 2 ) n —OH, —(CH 2 ) n NR 4 R 5 , -alkylene-R a where R a is selected from monofluorophenyl or monochlorophenyl, and branched isomers thereof wherein n is an integer from 1 to 8 inclusive and R 4 and R 5 are hydrogen or alkyl; and
then R 1 is not —S-alkyl,
B. in the compounds of formula (I), when
is a single bond,
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent, or one of R 2 and R 3 is ═CH 2 and the other is absent, with the provisos that both R 2 and R 3 are not hydrogen; when one of R 2 and R 3 is halo, the other is not hydrogen or hydroxy; and when one of R 2 and R 3 is hydroxy, the other is not hydrogen or hydroxy;
R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is selected from the group consisting of hydrogen and alkyl; and
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo;
then at least one of R 9 is other than hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, —(CH 2 ) n —OH, —(CH 2 ) n NR 4 R 5 , -alkylene-R a where R a is selected from monofluorophenyl or monochlorophenyl, and branched isomers thereof wherein n is an integer from 1 to 8 inclusive and R 4 and R 5 are hydrogen or alkyl,
C. in the compounds of formula (I), when
is a single bond,
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent, or one of R 2 and R 3 is ═CH 2 and the other is absent, with the provisos that both R 2 and R 3 are not hydrogen; when one of R 2 and R 3 is halo, the other is not hydrogen or hydroxy; and when one of R 2 and R 3 is hydroxy, the other is not hydrogen or hydroxy;
R 7 is selected from the group consisting of hydrogen and alkyl; and
R 1 is selected from the group consisting of —S-alkyl, —S-substituted alkyl, (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy and halo;
R 9 is independently selected from other than hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl, substituted phenyl, —(CH 2 ) n —OH, —(CH 2 ) n NR 4 R 5 , -alkylene-R a where R a is selected from monofluorophenyl or monochlorophenyl, and branched isomers thereof wherein n is an integer from 1 to 8 inclusive and R 4 and R 5 are hydrogen or alkyl,
then R 6 is selected from the group consisting of substituted alkyl (other than monosubstituted heterocycle or substituted heterocycle),
(carboxamido)alkyl, and an —N(R 6 )— fragment that is part of an amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
wherein, as used in these provisos only, the following specific terms have the following specific meanings:
substituted alkyl refers to alkyl groups wherein one or more of the hydrogen atoms has been replaced by a halogen, oxygen, hydroxy, amine (primary), amine (secondary-alkyl substituted by alkyl as above), amine (tertiary-alkyl substituted by alkyl as defined above), sulfur, —SH or phenyl),
substituted cycloalkyl refers to cycloalkyl substituted with an alkyl group, wherein alkyl is as defined above or a group wherein one or more of the hydrogen atoms has been replaced by a halogen, oxygen, hydroxy, amine (primary), amine (secondary-alkyl substituted by alkyl as above), amine (tertiary-alkyl substituted by alkyl as defined above), sulfur, —SH or phenyl,
substituted oxygen refers to the group —OR d where R d is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, allkenyl, cycloalkyl, and substituted cycloalkyl, substituted nitrogen or amino refers to the group —NR a R b wherein R a and R b are independently hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl,
substituted aryl refers to an aryl ring substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl where alkyl thio refers to the group —S-alkyl and thioalkyl refers to an alkyl group having one or more —SH groups, and
substituted heteroaryl refers to a heteroaryl ring substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl where alkyl thio refers to the group —S-alkyl and thioalkyl refers to an alkyl group having one or more —SH groups.
16. The compound of any of the claims 12 – 15 wherein the nitrogen-containing ring in Formulas (I) and (IA) is selected from:
17. A compound of Formula (IB):
wherein:
R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is H, alkyl, or hydroxyalkyl;
R 7 is H or alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, —(CH 2 ) n —OH, —(CH 2 ) n —NR 4 R 5 , and branched chain isomers thereof wherein n is an integer of from 1 to 8 inclusive and R 4 and R 5 are H or alkyl; and
m is 1 or 2;
or prodrugs and/or pharmaceutically acceptable salts thereof.
18. A compound of Formula (II):
wherein:
W is a nitrogen-containing ring:
m is 0, 1, 2, or 3; wherein when m is 2, the nitrogen-containing ring may optionally contain a double bond between the 4 and 5 nitrogen-containing ring positions; wherein when m is 3, the nitrogen-containing ring may optionally contain one double bond between either the 4 and 5 nitrogen-containing ring positions or between the 5 and 6 nitrogen-containing ring positions; wherein the nitrogen-containing ring positions are consecutively numbered counterclockwise beginning with “1” at the nitrogen;
R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, alkylsulfanyl, and substituted alkylsulfanyl;
R 20 and R 21 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 20 and R 21 is ═NOR 7 and the other is absent, or one of R 20 and R 21 is ═CH 2 and the other is absent; or R 20 and R 21 taken together are cycloalkyl, aryl, or heterocyclic group;
R 6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl, or —N(R 6 )— fragment is part of the amidine, N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;
R 7 is H or alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl, substituted arylsulfanyl, heteroarylsulfanylalkyl, heterocyclicsulfanylalkyl, heteroarylsulfanyl, and heterocyclicsulfanyl, propylidene (═CHCH 2 CH 3 ), azido, —(CH 2 ) n —OH, —(CH 2 ) n —NR 4 R 5 , and branched chain isomers thereof wherein n is an integer of from 1 to 8 inclusive and R 4 and R 5 are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl, substituted alkenyl, and —S(O) q R 13 where q is an integer equal to zero, one or two and R 13 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein not more than one —S(O) q R 13 group is present on the nitrogen-containing ring;
or a prodrug and/or pharmaceutically acceptable salt thereof.
19. A compound selected from the group consisting of:
4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-acetic acid methyl ester;
1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid ethyl ester;
4-(3-Cyano-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propylidene-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide; and
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Fluoro-phenylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3,3,3-Trifluoro-propylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2-Chloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methyl-butylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(2-Mercapto-ethoxy)-ethylsulfanyl]-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,2,2-Trifluoro-ethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyridin-4-ylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Trifluoromethoxy-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Butylsulfanyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-acetic acid methyl ester;
1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid ethyl ester;
4-(3-Cyano-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic acid phenyl ester;
4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propylidene-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
3-(3-Cyclobutyl-propyl)-azetidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide
4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide; and
4-(2-Cyclopropyl-ethyl)-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.
20. A compound selected from the group consisting of:
Phosphoric acid mono-(6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl) ester;
Phosphoric acid mono-(6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl) ester;
Phosphoric acid mono-(6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl) ester;
Phosphoric acid mono-(6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl) ester;
Hexadecanoic acid 6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester;
Hexadecanoic acid 6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester;
Hexadecanoic acid 6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester;
Hexadecanoic acid 6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl ester.
21. A compound selected from the group consisting of:
2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-propyl-azepane-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-fluoro-5-propyl-azepane-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
5-Fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-5-propyl-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
5-Cyclopropylmethyl-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-cyclopropylmethyl-azepane-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-fluoro-4-propyl-piperidine-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
4-Fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.
22. A compound of Formula (IB):
wherein:
R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl;
R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R 2 and R 3 is ═NOR 7 and the other is absent;
R 6 is H, alkyl, or hydroxyalkyl;
R 7 is H or alkyl;
R 9 , which can be singly or multiply substituted in the ring on the same or different carbons, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl, —(CH 2 ) n —OH, —(CH 2 ) n —NR 4 R 5 , and branched chain isomers thereof wherein n is an integer of from 1 to 8 inclusive and R 4 and R 5 are H or alkyl; and
m is 1 or 2;
or a prodrug and/or a pharmaceutically acceptable salt thereof;
with the proviso that the compound of formula I has a minimum inhibition concentration of 32 μg/mL or less against at least one of the organisms selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis, Bacteroides thetaiotaomicron , and Clostridium difficile.
23. A compound selected from the group consisting of:
4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-piperidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
1-(2-Hydroxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-piperidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Pentyl-pyrrolidine-2-carboxylic acid [1-(6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;
4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
Phosphoric acid mono-(4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl) ester;
Hexadecanoic acid 4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-yl ester;
Phosphoric acid mono-(4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl) ester;
Hexadecanoic acid 4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-yl ester;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;
2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-pyrrolidine-1-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;
4-Propyl-pyrrolidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Propyl-pyrrolidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Propyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-propyl]-amide;
4-Propyl-pyrrolidine-2-carboxylic acid {2-methyl-1-[3,4,5-trihydroxy-6-(2-methylsulfanyl-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;
4-Propyl-pyrrolidine-2-carboxylic acid [1-(6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;
or a prodrug and/or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 12 – 15 and 17 – 23 .
25. A method for the treatment of bacterial infection in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 12 – 15 and 17 – 23 .
26. A method for the treatment of bacterial infection in a mammal comprising administering to the mammal a pharmaceutical composition of claim 24 .
27. A method according to claim 26 for the treatment of bacterial infection caused by any of the following bacterial pathogens: H. influenzae, E. faecalis , and E. faecium.
28. The method according to claim 26 , wherein the compound is administered in an amount of from about 0.1 to about 100 mg/kg body weight/day.
29. The method according to claim 27 , wherein the compound is administered in an amount of from 0.1 to about 100 mg/kg body weight/day.Cited by (0)
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